1. Field of the Invention
The present invention relates to processes for preparing small particles, preferably spherical particles, usually in the range of about 1 to 30 microns, with the size controllable in narrow ranges of from 1-5 micrometers, 5-15 micrometers, or 15 to 30 micrometers. These particles, referred to herein as xe2x80x9cmicronized particles,xe2x80x9d have the advantage of controlled sizing, even size distribution of particles, controlled dissolution rates, and more consistent drug release properties. The invention also relates to new micronized particles obtained by the process of the invention and to their use in human or animal pharmacy. The present invention also relates to a process for the microfluidization of hydrophobic drugs and the use of the microfluidized product in a drug delivery system to provide controlled swellability and erosion-rate control. The drug release properties may also be modified as desired by using the microfluidization process to alter the product (pellet or particle) design or geometry.
2. Background of the Art
Bioavailability is the degree to which a drug becomes available to the target tissue after administration. Many factors can affect bioavailability including the dosage form and various properties, e.g., dissolution rate of the drug. Poor bioavailability is a significant problem encountered in the development of pharmaceutical compositions, particularly those containing an active ingredient that is poorly soluble in water. Poorly water soluble drugs, i.e., those having a solubility less than about 15 mg/ml or less than 10 mg/ml, tend to be eliminated from the gastrointestinal tract before being absorbed into the circulation. Moreover, poorly water soluble drugs tend to be unsafe for intravenous administration techniques, which are used primarily in conjunction with fully soluble drug substances.
It is known that the rate of dissolution of a particulate drug can increase with increasing surface area, i.e., decreasing particle size. Consequently, methods of making finely divided drugs have been studied and efforts have been made to control the size and size range of drug particles in pharmaceutical compositions. For example, dry milling techniques have been used to reduce particle size and hence influence drug absorption. However, in conventional dry milling, as discussed by Lieberman et al, Pharmaceutical Dosage Forms: Tablets, Volume 2, Chapter 3, xe2x80x9cSize Reductionxe2x80x9d, p. 132, (1990), the limit of fineness is reached in the region of 100 microns (100,000 nm) when material cakes on the milling chamber. Lachman et al note that wet grinding is beneficial in further reducing particle size, but that flocculation restricts the lower particle size limit to approximately 10 microns (10,000 nm). However, there tends to be a bias in the pharmaceutical art against wet milling due to concerns associated with contamination. Commercial airjet milling techniques have provided particles ranging in average particle size from as low as about 1 to 50 .mu.m (1,000-50,000 nm). However, such dry milling techniques can cause unacceptable levels of dust.
Other techniques for preparing pharmaceutical compositions include loading drugs into liposomes or polymers, e.g., during emulsion polymerization. However, such techniques have problems and limitations. For example, a lipid soluble drug is often required in preparing suitable liposomes. Further, unacceptably large amounts of the liposome or polymer are often required to prepare unit drug doses. Further still, techniques for preparing such pharmaceutical compositions tend to be complex. A principal technical difficulty encountered with emulsion polymerization is the removal of contaminants, such as unreacted monomer or initiator, which can be toxic, at the end of the manufacturing process. U.S. Pat. No. 4,540,602 (Motoyama et al) discloses a solid drug pulverized in an aqueous solution of a water-soluble high molecular substance using a wet grinding machine. However, Motoyama et al teach that as a result of such wet grinding, the drug is formed into finely divided particles ranging from 0.5 .mu.m (500 nm) or less to 5 .mu.m (5,000 nm) in diameter.
EPO 275,796 describes the production of colloidally dispersible systems comprising a substance in the form of spherical particles smaller than 500 nm. However, the method involves a precipitation effected by mixing a solution of the substance and a miscible non-solvent for the substance and results in the formation of non-crystalline nanoparticles. Furthermore, precipitation techniques for preparing particles tend to provide particles contaminated with solvents. Such solvents are often toxic and can be very difficult, if not impossible, to adequately remove to pharmaceutically acceptable levels to be practical.
U.S. Pat. No. 4,107,288 describes particles in the size range from 10 to 1,000 nm containing a biologically or pharmacodynamically active material. However, the particles comprise a crosslinked matrix of macromolecules having the active material supported on or incorporated into the matrix.
U.S. Pat. No. 5,145,684 discloses a process for preparing particles consisting of a crystalline drug substance having a surface modifier or surface active agent adsorbed on the surface of the particles in an amount sufficient to maintain an average particle size of less than about 400 nanometers. The process of preparation comprises the steps of dispersing the drug substance in a liquid dispersion medium and applying mechanical means in the presence of grinding media to reduce the particle size of the drug substance to an average particle size of less than 400 nm. The particles can be reduced in the presence of a surface active agent or, alternatively, the particles can be contacted with a surface active agent after attrition. The presence of the surface active agent prevents flocculation/agglomeration of the nanoparticles.
The mechanical means applied to reduce the particle size of the drug substance is a dispersion mill, the variety of which include a ball mill, an attrition mill, a vibratory mill and media mill, such as sand mill, and a bead mill.
The grinding media for the particle size reduction is spherical or particulate in form and includes: ZrO.sub.2 stabilized with magnesia, zirconium silicate, glass, stainless steel, titania, alumina and ZrO.sub.2 stabilized with yttrium. Processing time of the sample can be several days long. This patent is incorporated herein in its entirety by reference.
To a more limited extent the prior art also utilized microfluidizers for preparing small particle-size materials in general. Microfluidizers are relatively new devices operating on the submerged jet principle. In operating a microfluidizer to obtain nanoparticulates, a premix flow is forced by a high pressure pump through a so-called interaction chamber consisting of a system of channels in a ceramic block which split the premix into two streams. Precisely controlled shear, turbulent and cavitational forces are generated within the interaction chamber during microfluidization. The two streams are recombined at high velocity to produce shear. The so-obtained product can be recycled into the microfluidizer to obtain smaller and smaller particles.
The prior art has reported two distinct advantages of microfluidization over conventional milling processes (such as reported in U.S. Pat. No. 5,145,684, supra): substantial reduction of contamination of the final product, and the ease of production scaleup.
Numerous publications and patents were devoted to emulsions, liposomes and/or microencapsulated suspensions of various substances including drug substances produced by the use of microfluidizers. See, for example:
1) U.S. Pat. No. 5,342,609, directed to methods of preparing solid apatite particles used in magnetic resonance imaging, x-ray and ultrasound.
2) U.S. Pat. No. 5,228,905, directed to producing an oil-in-water dispersion for coating a porous substrate, such as wood.
3) U.S. Pat. No. 5,039,527 is drawn to a process of producing hexamethyhnelamine containing parenteral emulsions.
4) G. Gregoriadis, H. Da Silva, and A. T. Florence, xe2x80x9cA Procedure for the Efficient Entrapment of Drugs in Dehydration-Rehydration Liposomes ODRVs), Int. J. Pharm. 65, 235-242 (1990).
5) E. Doegito, H. Fessi, M. Appel, F. Puisieux, J. Bolard, and J. P. Devissaguet, xe2x80x9cNew Techniques for Preparing Submicronic Emulsionsxe2x80x94Application to Amphotericine-B,: STP Pharma Sciences 4, 155-162 (1994).
6). M. Lidgate, R. C. Fu, N. E. Byars, L. C. Foster, and J. S. Fleitman, xe2x80x9cFormulation of Vaccine Adjuvant Muramyldipeptides. Part 3. Processing Optimization, Characterization and Bioactivity of an Emulsion Vehicle,xe2x80x9d Pharm Res. 6, 748-752 (1989).
7) H. Talsma, A. Y. Ozer, L. VanBloois, and D. J. Crommelin, xe2x80x9cThe Size Reduction of Liposomes with a High Pressure Homogenizer (Microfluidizer): Characterization of Prepared Dispersions and Comparison with Conventional Methods,xe2x80x9d Drug Dev. Ind. Pharm. 15, 197-207 (1989).
8) D. M. Lidgate, T. Tranner, R. M. Shultz, and R. Maskiewicz, xe2x80x9cSterile Filtration of a Parenteral Emulsion,xe2x80x9d Pharm. Res. 9, 860-863 (1990).
9) R. Bodmeier, and H. Chen, xe2x80x9cIndomethacin Polymeric Nanosuspensions Prepared by Microfluidization,xe2x80x9d J. Contr. Rel. 12, 223-233 (1990).
10) R. Bodmeier, H. Chen, P. Tyle, and P. Jarosz, xe2x80x9cSpontaneous Formation of Drug-Containing Acrylic Nanoparticles,xe2x80x9d J. Microencap, 8, 161-170 (1991).
11) F. Koosha, and R. H. Muller, xe2x80x9cNanoparticle Production by Microfluidization,xe2x80x9d Archiv Der Pharmazie 321,680 (1988).
However, reports are few on reducing mean particle size (hereinafter sometimes abbreviated as MPS) of water-insoluble materials for use in pharmaceutical/diagnostic imaging compositions.
It is known from the prior art, described in Patent FR 2,608,988, to prepare particles smaller than 500 nm in size by at least three types of process. The first process type consists of polymerization of a monomer in a solution so as to obtain a micellar dispersion of the polymer in the solution. This first process type is limited to monomers which can be polymerized in solution. Moreover, it necessitates removal, after the polymerization step, of the polymerization catalyst, the low molecular weight oligomers, the monomers and the surfactants needed for the polymerization. The polymer obtained in this first process type has a random molecular weight distribution.
The second and third process types use preformed polymers, dissolving them in a solvent, forming a precipitate or a dispersion from a solution of these polymers and a non-solvent, and then evaporating off the solvent to recover the nanoparticles in the form of a colloidal suspension. The solvent solution is generally an organic solution of the polymer, and the nonsolvent solution is often an aqueous solution.
According to the second type of process, the polymer is dissolved in a water-miscible organic solvent. When the resulting solution is mixed with the aqueous phase, the polymer insoluble in the aqueous phase/organic solvent mixture precipitates in the form of nanoparticles.
According to the third type of process, a water immiscible organic solvent containing the polymer is emulsified in an aqueous phase, and the organic solvent is then evaporated off.
Formation of the precipitate or the emulsion requires the presence of a considerable amount of surfactant. It is very difficult to remove the surfactant remaining in the colloidal suspension during the subsequent evaporation to obtain the nanoparticles. Furthermore, the presence of a surfactant is often undesirable in the interest of good biocompatibility. Hence the latter two techniques cannot be used for the preparation of biocompatible nanoparticles because a colloidal protective agent is present.
FR 2,608,988 relates to a process for preparing dispersible colloidal systems in the form of nanoparticles smaller than 500 nm. These nanoparticles, based on a substance which can be a polymer and/or an active principle, are obtained by the second method mentioned above. The nanoparticles which are obtained, based on a polylactic polymer, contain an amount of surfactant equal to the amount of polymer in the majority of the examples. In only one example (Example 4) does the inventor claim to obtain nanoparticles of polylactic polymer without a surfactant. The Applicants reproduced this experiment and obtained nanoparticles of polylactic polymer from an acetone solution of polylactic acid and water with extremely low yields, always less than 10%. Hence this technique cannot practicably be used for the preparation of nanoparticles of polylactic acid in the absence of a surfactant.
U.S. Pat. No. 5,510,118 describes a process of preparing stable, dispersible, water-insoluble, drug nanoparticles consisting essentially of a crystalline drug substance having a surface modifier adsorbed on the surface thereof comprising the steps of:
a) dispersing a crystalline drug substance in a liquid dispersion medium containing a surface modifier, and
b) subjecting the liquid dispersion medium to the comminuting action of a microfluidizer asserting shear, impact and cavitation forces onto the crystalline drug substance contained in the liquid dispersion medium for a time necessary to reduce the mean particle size of said crystalline drug substance to less than 400 nm. The patent asserts that the particles can be formulated into pharmaceutical compositions exhibiting remarkably high bioavailability, the process provides a stable dispersion consisting essentially of a liquid dispersion medium and the above-described particles dispersed therein, and in a particularly valuable and important embodiment of the invention, there is provided a pharmaceutical composition comprising the above-described particles and a pharmaceutically acceptable carrier therefor. Such pharmaceutical composition is useful in a method of treating mammals. It is also an asserted advantage that a wide variety of surface modified drug nanoparticles free of unacceptable contamination can be prepared in accordance with this invention and that pharmaceutical compositions containing poorly water soluble drug substances are provided which are suitable for intravenous administration techniques. The particle size is therefore always reduced to less than 0.4 micrometers to assure rapid absorption of the active drug by the blood stream upon intravenous delivery.
U.S. Pat. No. 5,534,270 describes a process for preparing sterilized nanoparticulate crystalline drug particles comprising the steps of:
1) providing a drug substance having a solubility in water of less than 10 mg/ml
2) depyrogenating rigid grinding media having an average particle size less than 3 mm at from 200.degreexc2x0 C. to 300xc2x0 C. for from 6 to 20 hours
3) mixing the drug substance and rigid grinding media and autoclaving it from 100.degreexc2x0 C. to 150xc2x0 C. for 10 to 50 minutes and
4) adding a surface modifier to the autoclaved drug substance and rigid grinding media to a dispersion medium and wet grinding the drug substance sufficiently to maintain an effective average particle size of less than 400 nm. The particle size is therefore always reduced to less than 0.4 micrometers to assure rapid absorption of the active drug by the blood stream upon intravenous delivery.
The present invention describes a process for providing particles or crystal particles of pharmaceutically active agents that have low levels of water solubility (e.g., less than 15 mg/ml) by microfluidization of the pharmaceutically active agents. The particles of pharmaceutically active agents are provided in dimensions for use in oral ingestion of the pharmaceutically active agents where the particle size must be controlled within defined micron dimension ranges (e.g., above 0.5 microns [up to about 20 microns] or between 1.0 and 15 microns). In the presence of dextrins, particularly cyclodextrins, particle sizes even in the nanometer ranges (e.g., below 1000 nm, e.g., less than 500 nm, less than 400 nm, and between 20 and 1000, or between 30 and 500 nm are novel and may be produced according to the present invention (with or without the presence of surface active agents or surface modifying agents). The pharmaceutically active agents may be microfluidized in the absence of any other pharmaceutically active coingredients (e.g., excipients, binding agents, surfactants or surface modifying ingredients or with their use). One ingredient that has been found to be beneficial in microfluidization of some pharmaceutically active agents has been cyclodextrins, such as beta-cyclodextrin. These cyclodextrins are provided into the stream to be microfluidized as particles and remain as particles through the conclusion of the microfluidization process. The particle size distribution effected by this process is quite uniform and controllable.
Significant process advantages are provided by the use of the dextrins, and definite product advantages occur with the use of the dextrins. It is to be noted that the dextrin(s) is added to the hydrophobic pharmaceutical as a solid and at least some of the dextrin(s) remains as a solid throughout the entire microfluidization process. The dextrin may be left with the pharmaceutical drug in the dosage product or either physically removed or removed by differential dissolution in a liquid medium that is not a solvent for the pharmaceutical.